The synthesis and use of substituted imidazoles in pharmaceutical preparations useful in treating atherosclerosis and in lowering serum cholesterol has been disclosed. For example, EP 0 372 445 A1 discloses an antihypercholesterolemic agent having the formula: ##STR1## wherein the substituents (R1, R2, R3, R6, A, X, Y, and Z) are as disclosed therein for Formula (I). (See EP 0 372 445 A1, pp. 5-7).
Scheme 1, disclosed on page 9 of the European application, utilizes an imidazole as the starting compound and produces the antihypercholesterolemic agent as follows: ##STR2## wherein the substituents are as defined for Formula (I).
According to the scheme presented above, the esters of Formula (3) are hydrolyzed to the corresponding carboxylic acids of Formula (4) by methods well known in the art. The amides of Formula (5) are prepared by coupling the carboxylic acids of Formula (4) with a primary amine by amide bond forming reactions known in the art.
The problem is that the process represented by this reaction scheme is expensive because it is protracted and requires expensive omega-haloalkanoates such as ethyl 5-bromopentanoate (step 1). Furthermore, the use of omega-haloalkanoates at the outset of a multistep synthesis, increases the cost disadvantage of this process. A further disadvantage to the use of omega-haloalkanoates is that many are lachrymators and/or irritants. Yet another disadvantage is that step 3 needs expensive dehydrating agents or requires two reaction steps via the acid chloride. Finally, as shown in the examples of the European application, the overall yield of the compound of Formula (5) is only modest. The compound of Formula (5) is similar to the final product of the present invention.
The European application also describes an alternative reaction (Scheme 4) for preparing the amides of Formula (5) which in turn are used to prepare compounds of Formula (I). Alternative Scheme 4 is represented in the European application (p. 11) as follows: ##STR3## wherein the substituents are as described for Formula (I).
Without teaching how, EP 0 372 445 A1 suggests that alternatively the amides of Formula (5) can be prepared by the alkylation of Formula (1) or (2) with compounds of the formula: EQU M--(A')CONHR.sup.6 (II)
wherein M is a halogen or tosylate group; A' is a moiety having one less methylene group than A (as described for Formula (I); and R.sup.6 is as defined for Formula (I).
The European application merely alludes to this alternative alkylation step. It does not teach the preparation of M--(A')CONHR.sup.6 (designated compound II), nor does it indicate the efficiency, yield, or economy of the suggested alkylating compound II, M--(A')CONHR.sup.6.
We have found that tosylate esters of this formula (wherein M=tosylate group) decompose at ambient temperatures or more rapidly on heating. The comparative example herein shows that formation of the suggested tosylate esters of compound II occurs only slowly at room temperature. During the slow reaction at room temperature, the product begins to decompose even before the reaction is complete, thus yielding less than optimum amounts of product.
We have also found that the tosylate esters are difficult to purify and difficult to solidify. On the other hand, although the halogen compounds of Formula II (wherein M=halogen) can be derived from omega-haloalkanoyl chlorides, these materials are expensive to produce and many are lachrymators. Furthermore, the chloro analogs alkylate only slowly and incompletely.
What is needed to produce a high overall yield of compounds of formula (5) are reactive alkylating agents which are themselves rapidly formed and are capable of being obtained pure from inexpensive and readily available starting materials.